The present invention relates to processes for the preparation of (2R, 2-alpha-R, 3a)-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-1, 4-oxazine which is useful as an intermediate in the preparation of certain therapeutic agents. In particular, the present invention provides a process for the preparation of (2R, 2-alpha-R, 3a)-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-1,4-oxazine which is an intermediate in the synthesis of pharmaceutical compounds which are substance P (neurokinin-1) receptor antagonists.
The general processes disclosed in the art for the preparation of (2R, 2-alpha-R)-4-benzyl-2-[1-[3,5-bis(trifluoro-methyl)phenyl]ethoxy-1,4-oxazin-3-one result in relatively low and inconsistent yields of the desired product (see U.S. Pat. No. 5,719,147). In contrast to the previously known processes, the present invention provides more practical and economical methodology for the preparation of (2R, 2-alpha-R, 3a)-2-[1-[3,5-bis(trifluoromethyl)phenyl]-ethoxy-3-(4-fluorophenyl)-1, 4-oxazine in relatively high yield and purity.
It will be appreciated that (2R, 2-alpha-R, 3a)-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-1,4-oxazine is an important intermediate for a particularly useful class of therapeutic agents. As such, there is a need for the development of a process for the preparation of (2R, 2-alpha-R, 3a)-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-1,4-oxazine which is readily amenable to scale-up, uses cost-effective and readily available reagents and which is therefore capable of practical application to large scale manufacture.
Accordingly, the subject invention provides a process for the preparation of (2R, 2-alpha-R, 3a)-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-1,4-oxazine via a very simple, short, relatively inexpensive and highly efficient synthesis.
The novel process of this invention involves the synthesis of (2R, 2-alpha-R, 3a)-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-1, 4-oxazine. In particular, the present invention is concerned with novel processes for the preparation of a compound of the formula: 
This compound is an intermediate in the synthesis of compounds which possess pharmacological activity. In particular, such compounds are substance P (neurokinin-1) receptor antagonists which are useful e.g., in the treatment of psychiatric disorders, inflammatory diseases, and emesis.
The present invention is directed to processes for the preparation of (2R, 2-alpha-R, 3a)-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-1,4-oxazine of the formula: 
An embodiment of the general process for the preparation of (2R, 2-alpha-R, 3a)-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-1, 4-oxazine of the formula: 
comprises:
(1) contacting a compound of the formula: 
5 with a reducing agent to give a compound of the formula: 
(2) activating such compound with an activating agent to give a compound of the formula: 
(3) coupling such activated compound with a compound of the formula: 
in the presence of a Lewis acid to give a compound of the formula: 
(4) hydrogenation of such compound to give a compound of the formula: 
(5) dehydrogenation of such compound to give a compound of the formula: 
and (6) hydrogenation of such compound to give the compound of the formula: 
In Step (1) it is preferred that the reducing agent is a hydride reducing agent known in the art and it is more preferred that the reducing agent is di(iso-butyl)aluminum hydride (DIBAL). Preferred solvents for Step (1) comprise an organic solvent which is selected from toluene, tetrahydrofuran (THF), diethyl ether, diglyme, and methyl t-butyl ether, and mixtures thereof, wherein tetrahydrofuran, toluene and mixtures thereof are the more preferred organic solvents. In Step (1) it is preferred that the reaction is between about xe2x88x9270 and 25xc2x0 C., and preferably about xe2x88x9220xc2x0 C.
In Step (2) it is preferred that activation of the 2-hydroxy group is conducted via reaction with trichloroacetonitrile to provide the corresponding trichloroimidate (xe2x80x94CNCl3), or alternatively a halogenating agent to provide derivatives substituted with F, Cl, Br, or I, or an optionally substituted alkyl or aryl acid chloride or acid anhydride to provide the corresponding optionally substituted ester (xe2x80x94Oxe2x80x94COxe2x80x94R or xe2x80x94Oxe2x80x94COCF3 or xe2x80x94Oxe2x80x94COCCl3 wherein R is C1-6alkyl, substituted C1-6alkyl, phenyl or substituted phenyl).
Preferred activating conditions employ trichloroacetonitrile and a weak base such as potassium carbonate in an organic solvent which is selected from toluene, tetrahydrofuran (THF), diethyl ether, diglyme, and methyl t-butyl ether, and mixtures thereof, wherein tetrahydrofuran, toluene and mixtures thereof are the more preferred organic solvents. Activation is typically carried out at room temperature.
In Step (3) it is preferred that the Lewis acid is selected from boron trifluoride etherate, TMSOTf, titanium tetrachloride, tin tetrachloride, and the like. The solvent is typically an organic solvent which is selected from toluene, tetrahydrofuran (THF), diethyl ether, diglyme, and methyl t-butyl ether, and mixtures thereof, wherein tetrahydrofuran is the more preferred organic solvents The reaction is typically carried out at a temperature range of between about xe2x88x9250 and about 50xc2x0 C.
In Step (4) it is preferred that the hydrogenation catalyst is a palladium catalyst, such as selected from: palladium on carbon, palladium on alumina, palladium on barium sulfate, palladium on calcium carbonate, palladium on barium carbonate, palladium on strontium carbonate, palladium on silica, and palladium hydroxide on carbon (Pearlman""s catalyst). It is more preferred that the hydrogenation catalyst is palladium on carbon, especially 5% or 10% palladium on carbon. Optionally, the product from Step (3) is contacted with a strong inorganic or organic acid prior to conducting the hydrogenation. The acid is selected from hydrochloric, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid, trichloroacetic acid, oxalic acid, tartaric acid, citric acid, malic acid, benzoic acid, 4-nitrobenzoic acid, methanesulfonic acid, trifluoromethane sulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid and 4-toluenesulfonic acid, wherein the most preferred acids are hydrochloric acid, hydrobromic acid or 4-toluenesulfonic acid. It is preferred that the solvent for the hydrogenation comprises a solvent which is selected from the group of C1-C4 primary, secondary and tertiary alcohols, and water. Preferred solvents for the hydrogenation comprise methanol, ethanol, isopropanol, n-propanol, n-butanol, water, and mixtures thereof. More preferred solvents for the hydrogenation comprise methanol and mixtures of methanol and water. It is preferred that the temperature of the reaction mixture for the hydrogenation is from about 10xc2x0 C. to about 50xc2x0 C., wherein the most preferred temperature is about 20-25xc2x0 C. It is preferred that the pressure of hydrogen during the hydrogenation is from about 1 to about 150 psi, wherein the most preferred pressure is about 5 to about 50 psi.
In Step (5) the dehydrogenation is conducted under dehydrogenating conditions such as dibromouricil (DBU) and N-chlorosuccinimide. The solvent typically comprises a polar aprotic solvent, such as selected from acetonitrile, dimethylformamide, ethyl acetate, tetrahydrofuran, toluene, dichloromethane and the like. A preferred solvent is dimethylformamide. The reaction is typically carried out at a temperature range of between about xe2x88x9250 and about 50xc2x0 C. and preferably about 0xc2x0 C.
In Step (6) it is preferred that the hydrogenation catalyst is a palladium catalyst, such as selected from: palladium on carbon, palladium on alumina, palladium on barium sulfate, palladium on calcium carbonate, palladium on barium carbonate, palladium on strontium carbonate, palladium on silica, and palladium hydroxide on carbon (Pearlman""s catalyst). It is more preferred that the hydrogenation catalyst is palladium on carbon, especially 5% or 10% palladium on carbon. It is preferred that the solvent for the hydrogenation comprises a solvent which is selected from the group of C1-C4 primary, secondary and tertiary alcohols, and water. The solvent may also comprise a polar aprotic solvent selected from acetonitrile, dimethylformamide, ethyl acetate, tetrahydrofuran, toluene, dichloromethane and the like (such as may be present from the previous Step (5). Preferred solvents for the hydrogenation comprise methanol, ethanol, isopropanol, n-propanol, n-butanol, water, and mixtures thereof. More preferred solvents for the hydrogenation comprise methanol and mixtures of methanol and water. It is preferred that the temperature of the reaction mixture for the hydrogenation is from about 10xc2x0 C. to about 50xc2x0 C., wherein the most preferred temperature is about 20-25xc2x0 C. It is preferred that the pressure of hydrogen during the hydrogenation is from about 1 to about 150 psi, wherein the most preferred pressure is about 5 to about 50 psi.
An embodiment of the present invention concerns a process for the preparation of (2R, 2-alpha-R, 3a)-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-1,4-oxazine of the formula: 
which is outlined as follows: 
Another embodiment of the present invention concerns a process for the preparation of a compound of the formula: 
which comprises hydrogenation of a compound of the formula: 
to give the compound of the formula: 
In this embodiment it is preferred that the hydrogenation is catalytic hydrogenation. It is preferred that the hydrogenation catalyst is a palladium catalyst, such as selected from: palladium on carbon, palladium on alumina, palladium on barium sulfate, palladium on calcium carbonate, palladium on barium carbonate, palladium on strontium carbonate, palladium on silica, and palladium hydroxide on carbon (Pearlman""s catalyst). It is more preferred that the hydrogenation catalyst is palladium on carbon, especially 5% or 10% palladium on carbon. It is preferred that the solvent for the hydrogenation comprises a solvent which is selected from the group of C1-C4 primary, secondary and tertiary alcohols, and water. Preferred solvents for the hydrogenation comprise methanol, ethanol, isopropanol, n-propanol, n-butanol, water, and mixtures thereof. More preferred solvents for the hydrogenation comprise ethanol or methanol and mixtures thereof with water. It is preferred that the temperature of the reaction mixture for the hydrogenation is from about 10xc2x0 C. to about 50xc2x0 C., wherein the most preferred temperature is about 20-25xc2x0 C. It is preferred that the pressure of hydrogen during the hydrogenation is from about 1 to about 150 psi, wherein the most preferred pressure is about 5 to about 50 psi.
The (2R, 2-alpha-R, 3a)-2-[1-[3,5-bis(trifluoromethyl)phenyl]ethoxy-3-(4-fluorophenyl)-1,4-oxazine obtained in accordance with the present invention may be used as starting material in further reactions directly or following purification.
The starting materials and reagents for the subject processes are either commercially available or are known in the literature or may be prepared following literature methods described for analogous compounds. The skills required in carrying out the reaction and purification of the resulting reaction products are known to those in the art. Purification procedures include crystallization, distillation, normal phase or reverse phase chromatography.